CaV1.2 signaling complexes in the heart

doi:10.1016/j.yjmcc.2012.12.006

Journal of Molecular and Cellular Cardiology

Volume 58, May 2013, Pages 143-152

https://doi.org/10.1016/j.yjmcc.2012.12.006 Get rights and content

Abstract

L-type Ca^2 + channels (LTCCs) are essential for generation of the electrical and mechanical properties of cardiac muscle. Furthermore, regulation of LTCC activity plays a central role in mediating the effects of sympathetic stimulation on the heart. The primary mechanism responsible for this regulation involves β-adrenergic receptor (βAR) stimulation of cAMP production and subsequent activation of protein kinase A (PKA). Although it is well established that PKA-dependent phosphorylation regulates LTCC function, there is still much we do not understand. However, it has recently become clear that the interaction of the various signaling proteins involved is not left to completely stochastic events due to random diffusion. The primary LTCC expressed in cardiac muscle, Ca_V1.2, forms a supramolecular signaling complex that includes the β₂AR, G proteins, adenylyl cyclases, phosphodiesterases, PKA, and protein phosphatases. In some cases, the protein interactions with Ca_V1.2 appear to be direct, in other cases they involve scaffolding proteins such as A kinase anchoring proteins and caveolin-3. Functional evidence also suggests that the targeting of these signaling proteins to specific membrane domains plays a critical role in maintaining the fidelity of receptor mediated LTCC regulation. This information helps explain the phenomenon of compartmentation, whereby different receptors, all linked to the production of a common diffusible second messenger, can vary in their ability to regulate LTCC activity. The purpose of this review is to examine our current understanding of the signaling complexes involved in cardiac LTCC regulation. This article is part of a Special Issue entitled "Calcium Signaling in Heart".

Highlights

► Ca^2 + influx by L-type Ca^2 + channels trigger Ca^2 + release and cardiac contraction. ► We discuss how VGCC are regulated by GPCR via cAMP/PKA. ► VGCC form signaling complexes with β₂AR, Gs, adenylyl cyclase, and PKA. ► VGCC also associate with the protein phosphatases PP2A and PP2B. ► These complexes regulate channel activity in a highly localized manner.

Introduction

The proximity of the constituent components of a signaling pathway often plays a critical role in ensuring the speed, efficiency, and specificity of the functional responses they produce. This is especially true for the signaling mechanisms involved in regulating many different ion channels. Ion channels forming signaling complexes with kinase(s) and phosphatase(s) is a common theme [1]. While the localization of such signaling molecules is often achieved through direct protein-protein interactions, spatial organization can also be achieved indirectly via scaffolding proteins as well as the targeting of the relevant control elements to specific subcellular locations or lipid domains in the plasma membrane [1], [2], [3]. The spatial restriction of signaling also extends to aspects of those pathways that involve diffusible second messengers, such as cAMP. Accordingly, signaling complexes often include receptors and enzymes such as adenylyl cyclase that are responsible for second messenger production, as well as proteins such as phosphodiesterases (PDEs), which are involved in second messenger catabolism. The primary focus of this review will be on the signaling complexes important in maintaining the fidelity of L-type Ca^2 + channel responses involving protein kinase A (PKA) in the heart.

Section snippets

Ca^2 + channels in the heart

Ca^2 + is a potent second messenger that controls a variety of cellular functions [4], [5]. This is particularly true in the heart, where the influx of Ca^2 + through voltage-dependent Ca^2 + channels plays an essential role in regulating action potential duration, triggering myocyte contraction, and controlling gene transcription [6]. Thus, they are an important target for regulating cellular function by a number of different signal transduction pathways, including those involving PKA.

Molecular structure of L-type Ca^2 + channels

There are four types of LTCC, Ca_V1.1–1.4, each of which exists as a multimeric protein complex consisting of one of four different corresponding α₁ subunits (α₁1.1–1.4) together with auxiliary β, α₂δ, and γ subunits [7] (Fig. 1). The α₁ subunit forms the ion-conducting pore and defines the specific type of Ca^2 + channel. It consists of four homologous domains (I-IV) each containing six transmembrane segments (S1–S6) and a pore forming P-loop between segments 5 and 6. Ca_V1.2 is the predominant

Regulation of Ca_V1.2

The regulation of Ca_V1.2 has been extensively studied because of its central role in contributing to the electrical and mechanical properties of the heart. Influx of Ca^2 + through LTCCs is responsible for maintaining membrane depolarization during the plateau of the cardiac action potential. Subsequent inactivation then allows repolarization thus affecting action potential duration. In this way LTCCs play a critical role in determining refractory period duration, thereby ensuring that electrical

A kinase anchoring proteins

PKA is an inactive tetramer consisting of two regulatory (inhibitory) (R) and two catalytic (C) subunits. Distinct genes encode four R (RIα, β and RIIα, β) and three C subunits (Cα, β, and γ). Suppression of C subunit catalytic activity is released following the binding of two molecules of cAMP to each R subunit [124]. It is now widely accepted that AKAPs play an essential role in orchestrating many different cAMP-dependent signaling events by tethering PKA and other regulatory enzymes together

Lipid rafts, caveolae, and cavoeolin-3

An alternative mechanism for the assembly of signaling complexes associated with Ca_V1.2 is through the colocalization of proteins in specific membrane domains [2]. The tight packing of sphingolipids and cholesterol in the plasma membrane creates microdomains called lipid rafts. These cholesterol rich domains can assemble signaling proteins with ion channels [140], [141], [142]. Proteins associated with lipid rafts are resistant to detergent (Triton X-100) solubilization and can be found in the

Summary

PKA-dependent phosphorylation plays an essential role in LTCC regulation. However, the exact mechanism for this regulatory effect is still an area of active investigation. Current evidence supports the idea that it may involve phosphorylation of one or more residues on α₁1.2, which then disrupts the autoinhibitory effect of the distal C terminal region of this subunit.

Another important aspect of LTCC regulation is the interaction of Ca_V1.2 with PKA. There is evidence that AKAP5 and AKAP7 can

Conflict of interest

The authors declare that there is no conflict of interest.

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Review articleCaV1.2 signaling complexes in the heart

Abstract

Highlights

Introduction

Section snippets

Ca2 + channels in the heart

Molecular structure of L-type Ca2 + channels

Regulation of CaV1.2

A kinase anchoring proteins

Lipid rafts, caveolae, and cavoeolin-3

Summary

Conflict of interest

J Mol Cell Cardiol

Curr Opin Cell Biol

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

J Biol Chem

Cell

J Mol Cell Cardiol

Trends Pharmacol Sci

J Biol Chem

J Mol Cell Cardiol

Biophys J

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Mol Cell

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

Biophys J

J Biol Chem

J Biol Chem

Cell

FEBS Lett

J Biol Chem

J Biol Chem

J Biol Chem

Neuron

Neuron

J Biol Chem

FEBS Lett

Supramolecular assemblies and localized regulation of voltage-gated ion channels

Physiol Rev

Calcium signaling: a tale for all seasons

Proc Natl Acad Sci U S A

Cardiac excitation–contraction coupling

Nature

Structure and regulation of voltage-gated Ca2 + channels

Annu Rev Cell Dev Biol

Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release

Cardiovasc Res

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J Physiol

cAMP-dependent phosphorylation sites and macroscopic activity of recombinant cardiac L-type calcium channels

Mol Cell Biochem

Specific phosphorylation of a site in the full-length form of the alpha 1 subunit of the cardiac L-type calcium channel by adenosine 3′,5′-cyclic monophosphate-dependent protein kinase

Biochemistry

Molecular heterogeneity of calcium channel beta-subunits in canine and human heart: evidence for differential subcellular localization

Physiol Genomics

The roles of the subunits in the function of the calcium channel

Science

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J Physiol

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Am J Physiol

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Nat Rev Neurosci

Review article
Ca_V1.2 signaling complexes in the heart

Ca^2 + channels in the heart

Molecular structure of L-type Ca^2 + channels

Regulation of Ca_V1.2

Structure and regulation of voltage-gated Ca^2 + channels